Demyelinated axon degeneration is the major cause of irreversible neurological disability in patients with progressive multiple sclerosis (MS). Cuprizone (CPZ) administration for more than 12 weeks can model progressive MS in triggering chronic demyelination, neurodegeneration, astrogliosis and exacerbated microglia (MG) activation. MG are physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) signaling and can thus be almost completely eliminated from the brain using CSF-1R inhibitors like BLZ945. Our previous results show that continuous BLZ945 treatment attenuates demyelination but exacerbates axonal degeneration, whereas MG depletion followed by repopulation has been shown to normalize MG chronic activation. The present work aimed to compare the effects of continuous and intermittent BLZ945 treatment on chronically CPZ-demyelinated mice. Mice were fed either control or CPZ chow for 12 weeks and orally gavaged vehicle or BLZ every week (continuous) or every other week (intermittent) from the 5nd week. BLZ induced a reduction in the number of MG in all structures evaluated and equally attenuated demyelination in both protocols. Functional evaluation showed no significant differences across groups. In conclusion, the intermittent protocol failed to yield microglial repopulation, and future experiments with sparser BLZ945 treatment may help test our hypothesis. These studies may render therapies to effectively treat patients in progressive stages of MS.